Age and testosterone effects on responses to influenza infection and vaccination

描述（由申请人提供）：随着年龄的增长，男性循环睾酮水平下降，导致性功能下降、认知能力下降、代谢紊乱和心血管疾病风险增加。因此，临床上睾酮浓度较低的老年男性，以及某些年轻男性，都需要长期的睾酮替代治疗。在初步研究中，我们发现免疫系统也是睾酮的靶标，影响包括流感在内的传染病的预后。通过小鼠模型，我们发现，与睾酮循环浓度较高的年轻男性相比，低睾酮浓度，无论是内源性的老年男性还是由手术阉割（即性腺功能减退）引起的年轻男性，都会增加炎症，导致流感病毒感染后更高的发病率和死亡率。在本R21申请中，我们建议严格检验低循环睾酮浓度通过改变男性免疫反应导致流感易感性和疫苗效力的年龄相关变化的假设。我们进一步预测，睾丸激素水平低的年轻或老年男性的睾丸激素替代将预防流感感染并改善疫苗接种的结果。在Aim 1中，我们将确定男性年龄依赖性的睾酮降低是否会影响病毒复制的动力学和大小，以及对流感感染的炎症、细胞介导和肱骨免疫反应。我们还将确定用睾酮治疗是否能预防疾病，特别是老年男性。预防流感的疫苗接种是减少流感的最有效手段，但疫苗的效力随着年龄的增长而下降，尤其是在男性中。目的2将测试低睾丸激素水平的假设

DESCRIPTION (provided by applicant): With age, circulating testosterone levels decline in males, resulting in conditions ranging from decreased sexual function to cognitive decline, metabolic disorders, and increased cardiovascular disease risk. As a result, aged males, and in some cases young males with clinically low testosterone concentrations, are prescribed long-term testosterone replacement therapy. In preliminary studies, we found that the immune system also is a target of testosterone, affecting the outcome of infectious diseases, including influenza. Using a murine model, we show that low testosterone concentrations, either endogenously occurring in aged male or caused by surgical castration (i.e., hypogonadism) in young males, increase inflammation and result in greater morbidity and mortality following influenza virus infection as compared with young males that have high circulating concentrations of testosterone. In this R21 application, we propose to critically test the hypothesis that low circulating testosterone concentrations contribute to age-associated changes in susceptibility to influenza and in vaccine efficacy by altering immune responses in males. We further predict that testosterone replacement in either young or aged males with low testosterone levels will protect against influenza infection and improve the outcome of vaccination. In Aim 1, we will determine whether age-dependent reduced testosterone in males affects the kinetics and magnitude of virus replication as well as inflammatory, cell-mediated, and humeral immune responses to influenza infection. We will also establish whether treatment with testosterone protects against disease, particularly in older males. Vaccination against influenza is the most effective means for reducing influenza, yet the efficacy of vaccines declines with age, especially in males. Aim 2 will test the hypothesis that low testosterone levels reduce antibody responses to influenza vaccination and protection against lethal challenge with influenza viruses in males. Replacement of testosterone in either young or aged males with low testosterone levels should improve vaccine efficacy by directly altering humeral immune responses. During seasonal epidemics of influenza as well as during the recent H7N9 outbreak, a significant majority of the deaths occur in people over 65 years of age, with men being 2-times more likely to die than women. If testosterone replacement therapy provides significant protection for males against influenza, then this could provide an inexpensive supplemental therapeutic approach for saving lives and reducing disease burden during influenza epidemics and pandemics.